DESCRIPTION: (Applicant's Abstract) Chronic exposure to morphine-like drugs results in physical dependence and marked sensitivity to effects of opioid antagonists. Recent data indicate that pretreatment of rats with a single dose of morphine also increases dramatically sensitivity to opioid antagonists, as measured behaviorally. The proposed research will test the hypothesis that this phenomenon reflects acute physical dependence mediated primarily by the mu-opioid receptor, as well as derivative hypotheses and theoretical models. The pharmacological, neurochemical, and neuroanatomical bases of the phenomenon and its generality across species and drug class will be examined systematically. Several well-validated methodologies will be used in order to obtain converging evidence, for example, a) Drug discrimination: an animal model of subjective drug effects, with resolution to distinguish among effects mediated by different opioid receptors and to detect interoceptive stimuli associated with antagonist-precipitated opioid withdrawal. b) Autotitration intracranial self-stimulation: enables concurrent quantitation of effects of opioid drugs and drug withdrawal on operant responding and threshold for rewarding brain stimulation. c) In vivo microdialysis: a means of correlating behavioral measures with changes in extracellular levels of catecholamines in specific brain regions. d) Tail-flick test: a measure of pain threshold. Compared to chronic opioid dependence, acute dependence has received little research attention despite the fact that it is a robust phenomenon that occurs in humans as well as in laboratory animals. Acute agonist-induced sensitization to opioid antagonists appears to be an exquisite example of neuronal plasticity, reflecting the first hours of the drug-receptor interactions that lead to chronic physical dependence upon opioids.